The vertebrate MHC-based allorecognition system has revealed much about T-cell function, and is beginning to yield information about NK cell function. Our understanding of the evolution of T-cells and MHC genes stops at sharks. In order to understand what other self/nonself recognition systems might operate in transplantation and cancer immunity and also to track the evolutionary origins of vertebrate MHC, we have investigated a model organism - the protochordate Botryllus schlosseri. Botryllus undergoes a natural transplant fusion (of blood vessels between distinct individuals) or rejection. Like MHC-based rejection in vertebrates, rejection in Botryllus is determined by a single, highly polymorphic histocompatibility locus we have named Fu/HC. A principle function of the Fu/HC appears to be the limitation of chimera formation in the wild to siblings. We have shown that Botryllus chimeras share somatic totipotent as well as germline progenitors resulting in germ cell and somatic cell parasitism; a comparable vertebrate condition is fetuses sharing a common blood circulation, such as in freemartin cattle. The two objective of this project are to: 1) to clone the polymorphic Fu/HC genes; and 2) to clone vertebrate MHC homologues in the Botrylluss genome. We shall test the relation of 1) to 2), and hope eventually to understand how Fu/HC self/nonself recognition works, and whether it has homologues in vertebrates.
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